PHARMACOLOGICAL MODULATION OF HEAT-SHOCK FACTOR-1 BY ANTIINFLAMMATORYDRUGS RESULTS IN PROTECTION AGAINST STRESS-INDUCED CELLULAR-DAMAGE

The activation of heat shock genes by diverse forms of environmental a nd physiological stress has been implicated in a number of human disea ses, including ischemic damage, reperfusion injury, infection, neurode generation, and inflammation. The enhanced levels of heat shock protei ns and molecular chaperones have broad cytoprotective effects against acute lethal exposures to stress. Here, we show that the potent antiin flammatory drug indomethacin activates the DNA-binding activity of hum an heat shock transcription factor 1 (HSF1). Perhaps relevant to its p harmacological use, indomethacin pretreatment lowers the temperature t hreshold of HSF1 activation, such that a complete heat shock response can be attained at temperatures that are by themselves insufficient. T he synergistic effect of indomethacin and elevated temperature is biol ogically relevant and results in the protection of cells against expos ure to cytotoxic conditions.